Breast cancer is the most common malignancy associated with pregnancy, with an incidence of approximately 1 in 3000 pregnancies.1 Approximately 10% of women with breast cancer who are less than 40 years of age will be pregnant at diagnosis.2 This is likely to increase as women opt to delay childbearing. A delay in diagnosis, on the part of physician and woman alike, is thought to contribute to the advanced disease at presentation. This is, in part, attributed to the engorgement and physiological hypertrophy of the pregnant or lactating breast.
Pregnancy-associated breast cancer is defined as cancer diagnosed during pregnancy or up to 1 year postpartum. Because of the rising incidence of this challenging clinical condition and the limited clinical experience that most generalist obstetricians have in dealing with it, it is essential that obstetricians, surgeons and oncologists are familiar with developments in the clinical management of this disease. These management strategies should be based on a multidisciplinary team approach.
There is evidence to suggest there may be a transient increase in breast cancer during the first 3–4 years following pregnancy.3–5 In a population-based prospective study of 802 457 Norwegian women aged 20–56 years,5 a short-term increase in breast cancer after full-term pregnancy was observed, with a peak 3–4 years after the delivery. Early menarche and late age at first pregnancy are also associated with an increased risk of breast cancer.6
Pregnancy also increases the risk of breast cancer developing in carriers of BRCA1 and BRCA2 mutations. Carriers of these mutations who have children are significantly more likely to develop breast cancer by the age of 40 years than carriers who are nulliparous, with each pregnancy being associated with an increased risk of cancer.7 Having a baby at a young age does not appear to protect BRCA1/BRCA2 carriers against subsequent development of breast cancer.8
Most invasive breast cancers are classified as invasive ductal carcinoma not otherwise specified (IDC NOS), whereas about 25% are defined as histological ‘special types’.9 Axillary lymph node involvement is observed in two-thirds of pregnant women with breast cancer.10,11 A large proportion of breast tumours diagnosed during pregnancy are high grade and display lymphovascular invasion.10,11 The incidence of positive estrogen and progesterone receptors is often found to be low (<30%).12 It is thought that high levels of circulating steroid hormones during pregnancy may interfere with ligand-binding assays or down regulate estrogen receptors found in neoplastic cells and thus immunohistochemistry should be used for assessing tumour receptor status.13,14 The overexpression of HER2/neu (c-erbB-2) has been found in 28–58% of pregnant women, whilst that of p53 is approximately 33%.13,15 It should, however, be noted that HER-2/neu is expressed in many embryonal tissues during the normal pregnancy period.
The occurrence of placental metastases has been reported in the literature16 and, therefore, it is worthwhile assessing placental histology after delivery in all cases even if it appears macroscopically normal. In general, the presence of placental metastases indicates a poor maternal prognosis.
Breast cancer usually presents as a painless lump or thickening. Occasionally, the disease can present as a bloody discharge from the nipple,17,18 although this can also be due to benign neocapillary formation within the breast. Inflammatory breast cancer is a rare syndrome (<4% of cases) whereby women present with erythema and breast induration with or without a peau d'orange appearance. This presentation is caused by tumour embolisation of dermal lymphatics. The ‘milk-rejection’ sign has been described rarely in case reports and refers to the unexplained refusal of an infant to feed from a lactating breast that harbours an occult carcinoma.
The differential diagnosis of a breast lump in pregnancy is summarised in Box 1. Although 80% of breast masses are benign, any mass persisting for 2–4 weeks deserves detailed investigation.
(Box 1 )
[Differential diagnosis of a breast lump in pregnancy]
Ultrasonography is helpful in distinguishing solid from cystic lesions of the breast but it cannot differentiate benign from malignant lesions. It is an inexpensive choice of imaging for a pregnant woman with a palpable lump in the breast. Mammography is associated with a high false negative rate during pregnancy (up to 25%) due to physiological breast changes.19 A standard mammogram exposes the fetus to 0.001–0.01 mGy radiation, which is considered safe.20 The International Commission on Radiological Protection20 (ICRP, 2007) concluded that no detrimental effects of practical significance would be expected to occur in humans below a dose of at least 100 mGy.
Studies on the use of magnetic resonance imaging (MRI) of the breast in pregnancy are not available and its role has not been evaluated. MRI is associated with the risk of heating and cavitation injuries to the fetus.22 Additional problems include difficulties in positioning the pregnant woman on her abdomen as well as concerns over the safety of the intravenous contrast material used. This agent, a gadolinium derivative, is associated with fetal abnormalities in rats when given in high and repeated doses,23 although teratogenic effects have not been reported in humans.24
Further staging evaluation will depend on the clinical stage at presentation and includes chest radiography performed with maternal abdominal shielding, liver ultrasound and screening non-contrast MRI of the thoracic and lumbar spine to exclude bone metastases in symptomatic women. The employment of computed tomography and bone scans is not recommended during pregnancy because of concerns relating to exposure of the fetus to radiation and the need for contrast enhancement.25 Chest radiography is considered safe in pregnancy and exposes the fetus to approximately 0.01 mGy, which is well below the threshold dose.20
Interventional methods to establish diagnosis
A core needle or excisional biopsy is the gold standard for the diagnosis of breast cancer. If the mother is breastfeeding, suppression of lactation with cabergoline will reduce the risk of milk fistula or abscess formation. Fine needle aspiration may also be used for the initial evaluation of a breast mass and shows good sensitivity but carries a higher risk of false positive results during lactation and pregnancy. This is due to the presence of hyperproliferative cells present in mammary tissue during these conditions.
The pathologist should also be aware that the woman is pregnant in order to avoid misdiagnosis of these hyperproliferative changes.26 Core needle biopsy appears to be the most cost-effective diagnostic test because of its high sensitivity and specificity.27
The treatment regimens used will depend, to some extent, on the number of weeks of gestation that the mother presents at, as well as desire to continue the pregnancy. Figure 1 summarises the management of breast cancer in pregnancy according to the gestation period at presentation. Treatment involves surgery and chemotherapy, with radiotherapy being reserved for women diagnosed with breast cancer late in pregnancy and who are undergoing breast conservatory surgery. A multidisciplinary approach to treatment should be planned promptly in order to avoid the risk of disease progression. Nettleton and colleagues28 used a mathematical model to assess the risk of delaying systemic treatment in women with pregnancy-associated breast cancer. Using this model, a delay in systemic therapy of 1, 3 and 6 months for an early stage primary breast cancer with a 130-day doubling time increases the risk of axillary node involvement by 0.9%, 2.6% and 5.1%, respectively. For tumours with a 65-day doubling time these increases are 1.8%, 5.2% and 10.2% for 1, 3 and 6 month delays, respectively.
Modified radical mastectomy is the definitive procedure of choice in women with stage I–III disease.29 Breast surgery can be performed safely during all the trimesters of pregnancy with negligible risk to the fetus. Axillary lymph node dissection is recommended in all cases of invasive breast cancer.30 This is particularly important in pregnancy because of the high risk of nodal metastases; this is also an indication for postoperative chemotherapy. Despite reports of the efficacy and safety of sentinel lymph node biopsy,31,32 this procedure is not recommended in pregnancy because of concerns relating to the presence of radioactive technetium probes, which may pose theoretical risks to the fetus. Overall, breast-conserving surgery is not advisable in pregnant women.30 However, breast-conserving surgery with axillary node dissection may be offered to women who are diagnosed in the third trimester.33,34 In this situation, radiotherapy can be delayed until after delivery of the baby. Women undergoing wide local excision procedures should be warned that radiotherapy will be necessary to prevent local recurrence and that further surgery may be required if surgical margins are not disease-free. The maximum delay in initiating radiotherapy following breast-conserving surgery should be approximately 12 weeks, as delay in treatment increases the likelihood of axillary metastasis by 0.028–0.057% per day.28,35
Radiotherapy is generally not recommended during the first trimester of pregnancy because of adverse effects to the fetus. Radiation exposure to the fetus can be minimised by using precise radiation techniques, appropriate shielding of the abdomen and by substituting whole breast therapy with partial breast treatment.36 Radiotherapy has the potential to cause miscarriage, teratogenicity, microcephaly, fetal growth restriction, learning difficulties, induction of childhood malignancies and haematological disorders.
Pregnancy-associated breast cancer is usually associated with invasive and high-grade lesions, making chemotherapy necessary. Chemotherapy reduces the annual odds of recurrence of breast cancer by 37% and deaths by 27%.37,38 A 4–6 month course is usually offered to node-positive women or node-negative women with a tumour larger than 1 cm. Although there are significant physiological changes in pregnancy, because of a lack of data on dose adjustments, the drug regimens are similar to those used in non-pregnant women. Systemic chemotherapy is the treatment of first choice when women present with stage IV breast cancer; this is normally started after the first trimester.
The timing of chemotherapy is crucial. A delay in chemotherapy of >3 weeks following surgery is thought to be associated with a significant impact on the prognosis compared with early commencement of chemotherapy.39 The efficacy of a very late start in chemotherapy—for example, beyond 8 weeks—is unknown.
Chemotherapy is considered to be safe when used during the second and third trimesters of pregnancy. This has been demonstrated by two series of women reported from the MD Anderson Cancer Center40 and The Royal Marsden Hospital.41 The period between 10 days and 8 weeks after conception is the most vulnerable. There is a potential risk of fetal damage during this period and the use of cytotoxic agents during this time is associated with a 17% risk of fetal malformation and spontaneous abortion.42 Consequently, chemotherapy is contraindicated during the first trimester. After organogenesis, the eyes, genitals, haematopoietic system and central nervous system are still vulnerable and thus chemotherapy should only commence after 14 weeks of gestation.42 Cyclophosphamide, doxorubicin (formerly Adriamycin®) and fluorouracil (CAF), is the recommended combination of drugs used in adjuvant chemotherapeutic regimens. The adverse fetal effects of chemotherapeutic agents commonly used in the treatment of breast cancer are summarised in Table 1.
Table 1. Adverse fetal effects of chemotherapeutic agents used in the management of breast cancer
Chemotherapy may sometimes lead to preterm delivery, low birthweight, transient tachypnoea of the newborn and transient neonatal leucopenia. Maternal and infant leucopenia have been reported when chemotherapy is administered less than 3 weeks before delivery, hence it is advisable to withhold chemotherapy after 35 weeks of gestation in order to minimise the risks of sepsis and haemorrhage in the mother and newborn.12
Tamoxifen is a non-steroidal estrogen with both agonist and antagonist activity. Its use is recommended in premenopausal women with estrogen receptor-positive breast cancers and for the palliative treatment of metastatic disease. The use of tamoxifen in pregnancy has been reported to be associated with oculoauriculovertebral dysplasia(Goldenhar syndrome),48 as well as ambiguous genitalia.49 Its use is thus not recommended during pregnancy.
Nausea and vomiting associated with chemotherapy can be safely treated with 5HT3-serotonin antagonists or steroids, especially during the second and third trimesters of pregnancy. Ondansetron is considered a class B drug in the USA and is reported to have the longest safety record.50 Granulocyte colony-stimulating factor is also considered safe and can be given during pregnancy to provide haematological support and to reduce the risk of maternal sepsis from neutropenic adverse effects.51 Healthcare providers should constantly strive to provide psychological support to women and their families, which should be available consistently throughout the woman's pregnancy until completion of therapy.
Pregnancy monitoring and obstetric outcome
There is no evidence to suggest that women with pregnancy-associated breast cancer need additional antenatal care. However, it is standard practice to establish fetal well-being using ultrasound monitoring whilst chemotherapy is being administered. Approximately 40% of babies will experience low birthweight, which is usually due to fetal growth restriction or premature labour. Delivery may be considered after fetal lung maturity is achieved between 32 and 34 weeks of gestation or in cases where extended chemotherapy is considered during the last month of gestation. If delivery takes place before 36 weeks of gestation, administering betamethasone to the mother should be considered to maximise fetal lung maturity.
A multidisciplinary approach with the lead obstetrician, surgeon and oncologist is vital in the management of these women. In cases of preterm delivery, prompt liaison with the paediatric team is also essential. A referral to the obstetric anaesthetist may be considered in some cases. The mode of delivery depends upon the gestation, with caesarean section being reserved for the usual obstetric indications. Careful consideration should be given to thromboprophylaxis in these women as malignancy puts them at a higher risk of venous thromboembolism.
Lactation is usually contraindicated during chemotherapy since all agents used have been detected in breast milk. If milk secretion is maintained throughout chemotherapy, breastfeeding can be allowed 3–4 weeks after the last administered dose of chemotherapy.52 In some cases, tissue fibrosis secondary to radiotherapy may inhibit lactation on the affected side in future pregnancies.
The role of termination of pregnancy
There is no evidence to suggest that termination of pregnancy improves prognosis.6 The decision to end pregnancy is, to a large extent, a personal choice of the woman or the couple following extensive discussions with a multidisciplinary team. Termination of pregnancy can also be considered in cases of advanced disease stage, that is, stage III or IV, at the time of diagnosis early in the first trimester. In addition, pregnancy termination can also be advisable in cases of high grade and aggressive primary tumours where survival may be shorter than the time needed to complete the pregnancy.1
It has been a matter of debate whether maternal prognosis for breast cancer during pregnancy is worse or better compared with the non-pregnant state. Nevertheless, 5-year survival rates in recent studies vary between 40–73% in women with pregnancy-associated breast cancer.12,53 A prospective study14 comparing 40 pregnancy-associated breast cancer cases with 61 non-pregnant women with infiltrative breast carcinoma showed significantly better survival rates for the non-pregnant women. It has been postulated that there are intense modifications in cell proliferation, survival and angiogenesis during pregnancy as well as the postpartum period, which all potentially enhance tumour progression. Similar results have been shown by a small study from Norway of 20 women54 and a French study of 154 women.55 Additional factors contributing to a poorer prognosis are the significant delay in diagnosis and changes in breast tissue associated with pregnancy making timely diagnosis more difficult.
Pregnancy after treatment of breast cancer
Results from retrospective series and population-based studies have shown no adverse effect of subsequent pregnancies on the survival of women with a history of breast cancer. Women with a diagnosis of breast cancer are often advised to wait at least 2 years after treatment before they attempt to conceive.56,57 The 2-year wait is suggested as a guide and is based on anecdotal evidence.58 With advances in adjuvant chemotherapy, the time to relapse has now been shown to be more than 5 years for node-positive women,59 hence the previous recommendation to delay a further pregnancy for 2 years is questionable.58 Nevertheless, fertility rates after breast cancer treatment are often adversely affected, particularly after the age of 30, because of chemotherapy drugs causing a reduction in ovarian reserve.
Women with advanced stage IV disease are advised against subsequent pregnancy as their 5-year survival rate is only 15%. Women with stage III disease are advised to wait at least 5 years. Those women with recurrent stage I or II disease are also advised against future pregnancy in view of the intensity of further treatments required and the poor prognosis of the disease.1
Breast cancer in pregnancy is an uncommon illness but one which poses dilemmas for both women and their carers. Triple assessment with clinical examination, imaging and biopsy provides an accurate investigation of symptomatic breast cancer. Ultrasound is the safest imaging modality in pregnant women, but mammography can be performed if necessary. There are no randomised controlled trials regarding the optimum management of pregnancy-associated breast cancer. A multidisciplinary approach is recommended for clinical decision-making. Modified radical mastectomy with axillary node dissection is the surgical treatment of choice for women with early stage breast cancer. Chemotherapy is allowed after the first trimester but hormonal therapy is avoided during pregnancy. Those women with breast cancer diagnosed very early in pregnancy, or with rapid advancement of the disease, may opt for termination of pregnancy.